Learning and memory defines how animals interact with their environment. This process relies on experience-driven changes in synaptic connections, a phenomenon known as synaptic plasticity; disruption of this process is believed to underlie several cognitive and psychiatric disorders. Although synaptic plasticity is critical for learning and memory, the mechanisms by which memory is formed and stored in neural circuits remains poorly understood. The proposed studies address this knowledge gap by focusing on synaptic mechanisms by which contextual memory is encoded in CA3 pyramidal neurons of the hippocampus, a brain region with a central role in learning and memory. Among the excitatory inputs converging onto CA3 pyramidal neurons, the mossy fiber (MF) input from dentate gyrus granule cells is known to be required for the encoding of contextual memory. Using genetic tools recently developed by us, we were able to identify the specific group of CA3 neurons activated by contextual learning, and identified a learning-dependent synaptic modifications associated with these neurons. We hypothesize that this newly identified synaptic plasticity plays a critical role in contextual memory formation. This hypothesis will be tested using a combination of molecular, cellular, electrophysiological and behavioral approaches in mice. We will also identify molecular pathways that selectively modulate MF-CA3 synapses in the mouse hippocampus. The proposed research has the potential to generate conceptual breakthroughs in our molecular and cellular understanding of memory formation, and ultimately provide insights into mechanisms underlying cognitive and psychiatric impairments.